The cardiac sodium (Na) channel controls cardiac excitability and the velocity of impulse propagation as it initiates the cardiac action potential (AP). Accordingly, derangements of cardiac sodium channel function affect excitability in ways that may culminate in cardiac arrhythmias. Previous studies have shown many inherited arrhythmia syndromes to be caused by sodium channel dysfunction secondary to mutations in SCN5A, the gene that encodes the pore-forming α-subunit of the cardiac sodium channel (hNav1.5) in the cell membranes of the muscle cells of the heart (the myocytes).
Two examples of inherited arrhythmias are Brugada and long QT-3 syndromes, two allelic diseases caused by different mutations in SCN5A gene inherited by an autosomal dominant pattern with variable penetrance. Loss-of-function mutations in this gene lead to a loss of whole cell sodium current.
Both of these syndromes are ion channel diseases of the heart that manifest on surface electrocardiogram (ECG) by ST-segment elevation in the right precordial leads and prolonged QT(c) interval, respectively, with predilection for polymorphic ventricular tachycardia and sudden death, which may be the first manifestation of the disease.
Brugada syndrome (BrS), also known as Sudden Unexpected Death Syndrome (SUDS), is an autosomal dominant disease with an increased risk of sudden cardiac death. It usually manifests during adulthood with male preponderance. This syndrome is also characterized by a high occurrence of incomplete penetrance, so that many patients with a BrS causing mutation never develop symptoms of the disease. Thus, there is great difficulty and debate over determining which patients are likely to develop a life threatening arrhythmia and who may need preventive therapy.
The cause of death in Brugada syndrome is ventricular fibrillation. The episodes of syncope (fainting) and sudden death (aborted or not) are caused by fast polymorphic ventricular tachycardias or ventricular fibrillation. These arrhythmias appear with no warning. The current treatment options for Brugada Syndrome include implantable cardioverter-defibrillator (ICD) and drug therapy. The ICD continuously monitors the heart rhythm and will defibrillate an individual if ventricular fibrillation is noted and is the only known method for preventing sudden cardiac death. However, ICD's are costly, can inappropriately shock their recipients, and are known to cause complications especially at the lead site. Furthermore, an ICD is not able to prevent future arrhythmias since it does not treat the channel dysfunction that is the underlying source of the arrhythmia. Pharmacological treatments for BrS are also being explored. Studies show that delivery of the sodium channel blocker, quinidine, reduces the inducibility of arrhythmias in electrophysiological studies, but is also associated with side effects that caused some patients to stop the therapy.
In congenital long QT syndrome, the electrocardiogram QT interval is prolonged due to dysfunctional ventricular repolarization. LQT syndrome is associated with syncope and sudden death and causes 3000 to 4000 sudden deaths in children and young adults each year in the US alone. Variant 3 (LQT-3) is associated with mutations in SCN5A. Arrhythmias in LQT-3 mutation carriers are more likely to occur at rest, when heart rate is slow. Congenital long QT syndrome, a rare disease in which the QT interval of the electrocardiogram is prolonged due to dysfunctional ventricular repolarization, Long QT3 syndrome usually manifests in teenage years, although it can also manifest in adulthood.
In symptomatic patients of long QT-3 syndrome in whom the torsade de pointes is bradycardia-dependent or pause-dependent, a pacemaker could be used to avoid bradycardia and pauses and an implantable cardioverter defibrillator is indicated where arrhythmia is not controlled with pacemaker and beta-blockade. These methods, however, have the shortcomings discussed above.
Recent studies indicate that sodium channel dysfunction may also be involved in structural and acquired cardiac defects. (Tan, H L, 2006, J Cardiovac Electrophysiol 17:S151-S157). A study of congestive heart failure found that enhanced sodium currents may be one of the underlying causes of arrhythmia in congestive heart failure.
Heart failure is often defined as the inability of the heart to deliver a supply of oxygenated blood sufficient to meet the metabolic needs of peripheral tissues, both at rest and during exercise. See generally, Hutter, Jr., “Congestive Heart Failure”, in Scientific American: Medicine, Volume 1 (1:II), eds. Dale and Federman (Scientific American, Inc. 1994).
The American Heart Association (AHA) 2006 update on heart disease reported that 5 million Americans are believed to have symptomatic heart failure (HF), and 550,000 patients are newly diagnosed each year. The estimated direct and indirect cost of HF in the United States (U.S.) for 2006 will be ˜$29.6 billion. Heart failure is a disabling chronic disease and the most frequent discharge diagnosis for hospitalization among older adults. Despite the significant resources expended on the treatment of this disease, outcomes remain poor. The five-year survival for individuals diagnosed with heart failure is less than 50%, and in end-stage heart failure, the one-year survival may be as low as 25% regardless of medical therapy. One major cause of death in heart failure patients is cardiac arrhythmias.
Despite continuous improvements, the treatment of heart failure is at this time unsatisfactory. Although the foundation of this disease is represented by the decrease in cardiac contractility, only two classes of drugs are approved for use to increase cardiac force (i.e. positive inotropes), cardiac glycosides (like digoxin) and beta-adrenergic agonists (like dobutamine, amrinone or milrinone). Importantly, despite an effective relief of symptoms, the use of these agents has been associated with no change (digoxin) or an increase (beta-adrenergic agonists) in mortality.
Other classes of agents used in heart failure exert their beneficial effects by preventing the long term cardiac remodeling of ion channels seen in heart failure that results in high risks of arrhythmias or by interfering with renal and vascular contributory mechanisms, both of which suffer from negative effects on both physician confidence and patient compliance. The need for new, effective treatments is, therefore, evident.
In sum, there remains a need to develop effective treatments for cardiac arrhythmias caused by ion channel disorders that avoid the complications of ICD's and drug therapy, but also address the underlying causes of the conditions that increase the risk for such arrhythmias.